Hepatic carcinogens are potent inhibitors of liver cell nuclear RNA synthesis. The mechanisms responsible for these effects and the even more difficult problem of their relationship to the carcinogenicity of the particular chemicals is poorly understood. Previous work has suggested that the nuclear RNA polymerases may be a frequent target molecule the interaction with which is responsible for the observed effects on RNA metabolism. The present application proposes to continue our studies of the mechanism of inhibition of rat liver nuclear RNA synthesis by the hepatocarcinogens ethionine, N-hydroxy-acetylaminofluorene and dimethylnitrosamine. At the same time, the objective is to determine the immediate functional consequences of these effects on RNA metabolism and to determine if similar biochemical and functional changes occur during carcinogenesis. We will concentrate on RNA polymerase II. It will be purified to homogeneity from control and carcinogen-treated animals, and the nature of the specific step that is inhibited examined. The mechanism for these effects will be sought in the alkylation of the enzyme by DMN, the arylamidation by N-OH-AAF, and changes in the extent of phosphorylation by ethionine. The functional consequences with respect to the pattern of informational RNA molecules synthesized and their translation into proteins will then be studied and these changes related to altered patterns of certain inducible enzymes. With this as a basis, we then will be able to look for specific biochemical and functional consequences with respect to the polymerases and to RNA metabolism in the livers of animals exposed to carcinogenic regimens of the three chemicals under study.